1. Field of the invention
The present invention relates to the fields of neuropsychiatry and medical foods. More specifically, the present invention relates to methods for increasing de novo synthesis of neurotransmitters in vivo and treating neuropsychiatric and/or neurologic disorders, such as autism spectrum disorders and attention deficit disorder with or without hyperactivity, with the medical food L-methylfolate.
2. Description of the Related Art
The number of cases of autism spectrum disorders (ASDs), as of 2010, was estimated at 307,749 with a U.S. annual economic cost of over 9 billion dollars (www.fightingautism.com). The number of cases has increased from 15,580 in 1992 to 292,818 in 2008 for children ages 6 to 22 years old, or 337,795 if all children are included starting at 3 years old versus starting at 6 years old. This represents a cumulative growth in the number of cases of autism of 1779% (www.cdc.gov). Suggested etiologies for the increase in autism rates include: the increased attention received diagnostically, the influence of environmental factors, and finally the overall influence of genetics and susceptibility (1-4).
Attention deficit disorder with and without hyperactivity (ADD/ADHD) is considered by some to be closely related to the spectrum of autism (5-6). As of 2006, 4.5 million children, ages 5-17 years, have ever been diagnosed with ADD/ADHD. Three to seven percent of school age children suffer from ADHD. The diagnosis of ADHD has increased an average of 3% per year from 1997-2006. And, the cost of the illness (using a 5% prevalence rate) is estimated to be between $36 and $52 billion (7). The exact causes of ADD/ADHD, like autism spectrum disorders, are not known. Evaluation of the genetics, environmental factors, and level of diagnostic attention also suggests multifactorial causes similar to autism spectrum disorders (8-10).
Despite the prevalence of autism spectrum disorders and attention deficit disorders, research to this point has not revealed consensual or conclusive etiologies to direct more effective and consistent treatment modalities. To better address effective treatment regimens, it may be necessary to revisit the suspected mechanisms of illness. This would best be done by evaluating the biochemical pathology of these illnesses, specifically evaluating the role of neurotransmitters.
Dopamine, norepinephrine, and serotonin are neurotransmitters critical to maintaining basic neurological and psychological balance in the human brain. Dopamine and norepinephrine are essential to maintaining alertness, attention, impulse control and executive functions. Serotonin is directed toward the control of appetite, sleep, memory and learning, temperature regulation, and mood and behavior. The clinical symptoms associated with ADHD and autism spectrum disorders reflect the imbalance in these neurotransmitters, not alone, but in conjunction with each other.
Medications currently used in the treatment of ADHD and autism spectrum disorders function to maintain this neurotransmitter balance. Dopamine and norepinephrine are prevented from uptake through various formulations of stimulants; serotonin, by selective serotonin reuptake inhibitors (SSRIs). In the case of ADHD, a deficiency of dopamine and norepinephrine is implicated. In autism, the deficiency likely involves all neurotransmitters, but primarily serotonin. The primary dilemma in clinical medicine is how to treat these conditions on the wide spectrum in which they exist.
In order to better treat the symptoms of this broad spectrum of neuropsychiatric disorders, it would be beneficial to identify a common point of therapy. One such point may be found in the enzyme methylenetetrahydrofolate reductase (MTHFR). Methylenetetrahydrofolate reductase is critical for the conversion of dietary folate to L-methylfolate. L-methylfolate is the active form of folate used in the brain for the formation of neurotransmitters. This enzyme is, in turn, encoded by the methylenetetrahydrofolate reductase gene for which exist multiple gene forms or polymorphisms.
In studies looking at the function of methylenetetrahydrofolate reductase polymorphisms, mutations have been implicated to encode this critical enzyme in a deficient manner (11). The deficient or reduced activity of methylenetetrahydrofolate reductase results in lower levels of L-methylfolate in the brain. A critical relationship exists between folate metabolism and methionine biosynthesis at the intersection point of the functional methylenetetrahydrofolate reductase enzyme. This junction in folate metabolism is critical for proceeding to the production of single methyl groups in methionine biosynthesis for DNA and downstream onto neurotransmitter synthesis.
In a normal functioning folate pathway, this transfer of methyl groups occurs via an irreversible reduction of 5,10-MTHF to L-methylfolate. The methyl trap, a commonly accepted hypothesis in biochemistry, also refers to this critical step in folate metabolism and supports an irreversibility that occurs by design. In vitamin B12 deficiency or related conditions, e.g. pernicious anemia, L-methylfolate accumulates due to an inability to transfer the methyl group to homocysteine by the B12 coenzyme-dependent transferase. The methyl groups are “trapped” as L-methylfolate in this condition. And, this critical step is unable to proceed due to lack of vitamin B12 and unable to reverse the pathway because of the irreversible reduction. Research reveals an abnormal “reversibility” that may occur at this critical step as a result of this dysfunctional or polymorphic form of the methylenetetrahydrofolate reductase enzyme.
A study by Goin-Kochel et al. analyzed a population of 147 children with autism spectrum disorders and methylenetetrahydrofolate reductase polymorphisms. The data on the children were taken from the Autism Genetic Resource Exchange (ACRE) and met strict criteria for autism, and the children had been evaluated for the methylenetetrahydrofolate reductase 677C>T polymorphism. Additionally, the study examined the use of vitamins/supplements including folate, but given the limited use of the supplements in the study population it was not believed that the supplementation would alter the data analysis. This study helps to clarify the genetic association of the methylenetetrahydrofolate reductase polymorphisms with autism spectrum disorders (12).
In evaluating the study population for the hypothesized deficiency in CSF folate, the primary limitation in determining potential response to folate is the lack of available serum analysis which could reflect a CSF deficit. James et al reported on methionine cycle and transsulfuration metabolites when evaluating 20 autistic children and their controls. The results revealed significant differences between case and control, but values were not out of the accepted normal range for the same values. Folate metabolites were not measured specifically (13). Another study by Moore, et al has demonstrated the clinically significant differences between interstitial fluids of muscle when compared to serum values for the same metabolites. It is hypothesized that the elusiveness to the etiology and treatment of autism spectrum disorders and ADHD may be attributed to similar discrepancies when comparing serum and CSF measures of folate and its metabolites and significant cofactors including vitamin B12.
Commercial use of L-methylfolate as an approach to folate supplementation has been used in prenatal care because, for example, low folate status may be involved in neural tube defects, pregnancy miscarriage, low fetal birth weight and age-related high risk complications of pregnancy, homocysteine management, and the treatment of depression, dementia and cardiovascular diabetic neuropathy conditions. L-methylfolate has been developed and are marketed under the brand names Metafolin®, Cerefolin NAC®, Deplin®, Metanx®, Neevo® and Zervalx®.
In the absence of treatment modalities for MTHFR polymorphisms or pathologies arising from other downstream defects in folate metabolism with or without the presence of an MTHFR polymorphism being present, unique approaches to the treatment of associated neuropsychiatric disorders are needed. Thus, a recognized need is still present in the art for effective therapeutic methods to alleviate or treat neuropsychiatric disorders, such as, but not limited to, autism spectrum disorders and attention deficit disorders. The present invention fulfils this longstanding need in the art.